Local activation of inflammatory cells in the brain may contribute to neuronal death that occurs following acute brain injury as well as more progressive degenerative processes. In this network, various cells communicate and regulate complex processes of initiation, propagation, and suppression of immune and inflammatory responses. Through the resident immune cell network and the cell-cell interactions between the neurons and the glia a cascade of responses occur upon insult that signal events that may lead to neuronal death. The purpose of this project is to identify the critical features of the glia response that may either cause or exacerbate an ongoing process of neuronal death. These features include not only the individual cell response but also the extracellular environment that may influence the outcome of such responses. We have determined that the inflammatory response in the brain serves much the same was as that in the periphery. As a host defense response it serves to protect the brain however, when the response becomes dysregulated this can lead to adverse events. Under this framework we have reported that microglia cells are critical not only in the initial phase of the damage response but also in the repair process following injury. During this process both the up-regulation of tumor necrosis factor and the regulation of microglia cells via cell cycle processes appear to be critical factors . In the active process of neuronal death induced by the organo-metal, trimethyltin, we characterized a dramatic generation of new neurons for replacement. The level of repair is substantial and occurs within an environment of high inflammatory signals. Through this network, various cells communicate and regulate complex processes of initiation, propagation, and suppression of immune and inflammatory responses. Over the past year we have continued our studies using this chemical-induced model of hippocampal neuronal damage and have characterized the molecular signals that occur prior to evidence of neuronal insult in addition to identifying the morphological and cellular responses that occur early in the microglia. These studies support a positive role for "inflammation" in providing a stimulating environment for neuronal repair and we plan to continue our examination of this model at the gene expression level using cDNA microarray analysis and other techniques as cell as immmunohistochemical techniques to localize the cells responsible for repair and regeneration. Such studies offer the promise of identifying the critical signal conditions to enhance endogenous neurogenesis which may be applicable to acute injuries such as stroke, head trauma and therapeutic approaches for more progressive neurodegenerative disorders.